RESUMO
Androgen receptor (AR) contributes to the progression of glioblastoma (GBM), and antiandrogen agents have the potential to be used for the treatment of GBM. However, AR mutation commonly happens in GBM, which makes the antiandrogen agents less effective. Heat shock 27 kDa protein (HSP27) is a well-documented chaperone protein to stabilize ARs. Inhibition of HSP27 results in AR degradation regardless of the mutation status of ARs, which makes HSP27 a good target to abolish ARs in GBM. Compound I is a HSP27 inhibitor that significantly induces AR degradation in GBM cells via the proteasomal pathway, and it selectively inhibits AR-overexpressed GBM cell growth with IC50 values around 5 nM. The compound also significantly inhibits in vivo GBM xenograft at 20 mg/kg and does not cause toxicity to mice up to 80 mg/kg. These results suggest that targeting HSP27 to induce AR degradation in GBM is a promising and novel treatment.
Assuntos
Antagonistas de Androgênios/farmacologia , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas de Choque Térmico HSP27/antagonistas & inibidores , Receptores Androgênicos/efeitos dos fármacos , Antagonistas de Androgênios/toxicidade , Animais , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Humanos , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Mutação , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Receptores Androgênicos/genética , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Previously synthesized tubulin inhibitors showed promising in vitro selectivity and activity against Human African Trypanosomiasis. Current aim is to improve the ligand efficiency and reduce overall hydrophobicity of the compounds, by lead optimization. Via combinatorial chemistry, 60 new analogs were synthesized. For biological assay Trypanosoma brucei brucei Lister 427 cell line were used as the parasite model and for the host model human embryonic kidney cell line HEK-293 and mouse macrophage cell line RAW 264.7 were used to test efficacy. Of the newly synthesized compounds 5, 39, 40, and 57 exhibited IC50s below 5⯵M inhibiting the growth of trypanosome cells and not harming the mammalian cells at equipotent concentration. Comparably, the newly synthesized compounds have a reduced amount of aromatic moieties resulting in a decrease in molecular weight. Due to importance of tubulin polymerization during protozoan life cycle its activity was assessed by western blot analyses. Our results indicated that compound 5 had a profound effect on tubulin function. A detailed structure activity relationship (SAR) was summarized that will be used to guide future lead optimization.